The use of keratinocytes from genetically null mice has provided insights in several pathways relevant to cancer pathogenesis. Activation of the ras oncogene in keratinocytes lacking the epidermal growth factor receptor (EGFR) produces small papillomas in vivo that show aberrant DNA synthesis in the suprabasal compartments. In contrast ras activation in keratinocytes deficient in p21waf1 produces papillomas with similar conversion frequencies and growth rates as papillomas derived from control keratinocytes. This differs from papillomas derived from p53-/- keratinocytes that progress rapidly to carcinomas suggesting that p53 functions other than control of p21waf1 contribute to tumor suppression. Similarly, cell lines derived from p53-/- keratinocytes form anchorage independent colonies after ras activation whereas parallel cell lines reconstituted with wild-type p53 will not grow in suspension after ras activation. Differential display analysis using keratinocytes from p53- /- and p53+/+ mice revealed a previously unidentified p53 dependent gene that also is regulated by TNF alpha, suggesting convergence of two tumor suppressor pathways in squamous neoplasia. Additional studies with TGF beta 1-/- keratinocytes, that also progress rapidly to carcinomas after ras activation, show that loss of TGF beta 1 is associated with genomic instability in vitro. TGF beta 1 null keratinocytes transformed by v- rasHa progress rapidly to aneuploidy after only several weeks of culture. These cells are also sensitive to malignant conversion in vitro after treatment with chemical carcinogens. Suppression of papilloma formation in mice treated topically with carcinogens together with retinoic acid may result from upregulation of TGF beta 1 in the tumor mass. Malignant conversion of papillomas resistant to retinoic acid suppression may result from tumor cells that have become resistant to TGF beta. Analysis of the genetic basis for susceptibility to skin tumor formation comes from crosses of inbred SENCAR (sensitive) mice with BALB/c resistant) mice. Analysis of backcross progeny by genome scan with 88 microsatellite markers identified loci on mouse chromosomes 5, 9 and 11 that contribute to sensitivity or resistance. Loss of heterozygosity within the susceptibility loci on chromosomes 5 and 9 in papillomas and carcinomas suggest these loci may harbor tumor suppressor genes.